CN103373940B - Novel process for synthesizing N-FMOC-amino acid crude product of non-active side chain - Google Patents
Novel process for synthesizing N-FMOC-amino acid crude product of non-active side chain Download PDFInfo
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Abstract
The invention discloses a method for synthesizing N-FMOC-amino acid crude product of non-active side chain. The method comprises the following steps: 1) dissolving an N-FMOC-amino acid crude product in an ethanol/water system to prepare an N-FMOC-amino acid solution, oscillating at a condition of 60-80 DEG C to completely dissolve the N-FMOC-amino acid crude product; 2) putting the solution obtained in the step 1) under a low temperature condition to crystallize N-FMOC-amino acid, filtering the crystallization mother liquor, fully washing the crystal through the ethanol/water system prepared in the step 1), and drying to obtain a pure N-FMOC-amino acid crystal product; and 3) putting the residual solvent after filtering the N-FMOC-amino acid crystal in the step 2) in a distilling apparatus to recycle ethanol.
Description
Technical field
The present invention relates to a kind of novel process of the N-FMOC-coarse amino acid crystallization for non-active side chain, also relate to the N-FMOC-amino acid crystallizes body obtained by the method purifying.
Background technology
In recent years, China's polypeptide and protein drug researchdevelopment are rapid, and particularly many have special bioactive polypeptide and present using value more widely, and the method for Peptide systhesis is mainly main method with solid-phase synthesis at present.Amino and side chain reactive group all needs to protect connecing in reactive polypeptide, sloughs blocking group again, otherwise amino acid whose misconnection and many side reactions can occur after improvement on synthesis.FMOC, namely fluorenes methoxy carbonyl acyl group is a kind of more common n terminal amino acid blocking group, and N-FMOC-amino acid, as common N protected amino acid, is the most basic raw material that solid-phase synthesis prepares polypeptide.
N-FMOC-amino acid preparation process roughly can be divided into two stages, i.e. the later-period purification of N-FMOC-Amino acid synthesis and its product.In later-period purification process, generally first add water after the completion of reaction, with Fmoc-Cl remaining in anhydrous diethyl ether aqueous phase extracted; Acid adding adjusts aqueous pH values to be 2, separates out object N-FMOC-amino acid, and is extracted with ethyl acetate; Then add anhydrous slufuric acid protactinium withhold excessive moisture content, remove ethyl acetate with rotary evaporation, obtain N-FMOC-coarse amino acid, last organic solvent recrystallization or precipitation N-FMOC-amino acid fine work.EAtherton etc. (1989) apply ethyl acetate, sherwood oil, dimethyl formamide ether and methylene dichloride-pumice wet goods recrystallization obtain the crystallization of N-FMOC-α-amino-isovaleric acid, N-FMOC-Isoleucine (N-FMOC-L-Ileu-OH), N-FMOC-methionine(Met) N-FMOC-L-Met-OH), FMOC-Histidine (FMOC-L-His-OH); Du Xiumin (2004), in " preparation research of Fmoc series protected amino acid ", uses the precipitation of methylene dichloride/petroleum ether system or ethyl acetate/petroleum ether system or crystallization process to separate out the sweet amino acid of N-FMOC-(N-FMOC-Gly-OH), N-FMOC-L-leucine (N-FMOC-Leu-OH) or FMOC-L-Isoleucine (N-FMOC-L-Ileu-OH); Flood a large bell abundant grade (2006) application recrystallisation from isopropanol is refined Cbz2Arg (Pbf) 2OHCHA; Zhao Pingping etc. (2008) apply sherwood oil crystallization process and refine Fmoc His (Trt) OH.
From above-mentioned existing research, because N-FMOC-coarse amino acid mainly applies sherwood oil or other organic solvent to fine work crystallization or separation method, be not difficult to find out although these organic solvent crystallization effects are better, but all to there is larger toxicity.Nearly 8000 tons of China's current FMOC-amino acid production, need nearly 3,200,000 tons of the organic solvents such as sherwood oil, although sherwood oil can repeat to reclaim after crystallization FMOC-amino acid, but in order to ensure the purity of FMOC-amino acid crystallizes, only repeatedly reclaim 1-2 time under normal circumstances, so, in FMOC-amino acid preparation process, create a large amount of organic liquid wastes.Therefore, research green, environmental protection, economic novel dissolvent and method urgently need key problems-solving at present.
Therefore, guaranteeing under N protected amino acid purification purity prerequisite, a kind of more green, environmental protection is being provided, the novel process of N-FMOC-coarse amino acid crystallization that has more economy become the emphasis studied at present in this field.
Summary of the invention
Based on above-mentioned technical problem, an object of the present invention is to provide a kind of adopt ethanol/water system to substitute method that traditional noxious solvent system based on sherwood oil carries out the crystallization of N-FMOC-coarse amino acid, said method comprising the steps of:
1) N-FMOC-coarse amino acid is dissolved in the ethanol/water system (ethanol: water=1 ~ 4: 1 ~ 5) be prepared into, be mixed with the N-FMOC-amino acid solution that concentration is 22 ~ 55 (g/l), under 60 ~ 80 DEG C of conditions, vibration makes it dissolve;
2) N-FMOC-amino acid crystallizes is made under being placed on cold condition, suction filtration crystalline mother solution, the abundant wash crystallization of ethanol/water system be prepared into by step 1, and dry N-FMOC-amino acid crystallizes sterling;
3) by step 2) in residual solvent after suction filtration N-FMOC-amino acid crystallizes, be placed in water distilling apparatus, Distillation recovery ethanol.
Another object of the present invention is to provide the N-FMOC-amino acid crystallizes that a kind of method of carrying out the crystallization of N-FMOC-coarse amino acid by above-mentioned ethanol/water system obtains.
Adopt ethanol/water system to substitute traditional noxious solvent system based on sherwood oil in the present invention and carry out the crystallization of N-FMOC-coarse amino acid, and after suction filtration N-FMOC-amino acid crystallizes, application distillation method reclaims the alcohol solvent in filtrate, ethanol recovered frequency can reach tens of times, with regard to N-FMOC-coarse amino acid crystallization operation, can reach the standard of " zero release ", be a kind of green, environmental protection, economic technique.
N-FMOC-amino acid crystallizes prepared by the present invention, the more commercially available N-FMOC-amino acid products of its purity, purity >=99% under high performance liquid phase 254nm wavelength, crystalline form is more neat.
Accompanying drawing explanation
Fig. 1 .N-FMCO-L-L-Ala-irregular large sheet crystal structure form signal
Spectrogram under Fig. 2 .N-FMCO-L-L-Ala-high performance liquid phase 254nm wavelength
Fig. 3 .N-FMCO-L-leucine-rectangle huge crystal structure form schematic diagram
Fig. 4 .N-FMCO-L-leucine--spectrogram under high performance liquid phase 254nm wavelength
Fig. 5 .N-FMCO-L-Isoleucine-long fine acicular macrocrystal crystal habit schematic diagram
Spectrogram under Fig. 6 .N-FMCO-L-Isoleucine-high performance liquid phase 254nm wavelength
The thick bar-shaped macrocrystal crystal habit schematic diagram of Fig. 7 .N-FMCO-L-methionine(Met)-length
Spectrogram under Fig. 8 .N-FMCO-L-methionine(Met)-high performance liquid phase 254nm wavelength
Fig. 9 .N-FMCO-L-glycine-length thin rhabdolith crystal habit schematic diagram
Spectrogram under Figure 10 .N-FMCO-L-glycine-high performance liquid phase 254nm wavelength
Figure 11 .N-FMCO-L-phenylalanine-length bar-shaped macrocrystal crystal habit schematic diagram
Spectrogram under Figure 12 .N-FMCO-L-phenylalanine-high performance liquid phase 254nm wavelength
The thin bar-shaped macrocrystal crystal habit schematic diagram of Figure 13 .N-FMCO-L-α-amino-isovaleric acid-length
Spectrogram under Figure 14 .N-FMCO-L-α-amino-isovaleric acid-high performance liquid phase 254nm wavelength
Figure 15 .N-FMCO-L-proline(Pro)-rectangle thin bulky crystal crystal habit schematic diagram
Spectrogram under Figure 16 .N-FMCO-L-proline(Pro)-high performance liquid phase 254nm wavelength
Embodiment
Below in conjunction with the drawings and specific embodiments, the present invention is described in further detail:
embodiment 1FMCO-L-L-Ala purification process
(1) ethanol/water system solution prepares: according to the requirement of object N-FMOC-L-third amino acid crystallizes, preparation ethanol/water=3: 2 system solutions.
(2) attemperator prepares: in water bath, add appropriate water, after switching on power, and setting water bath temperature, and be heated to setting 80 DEG C.
(3) N-FMOC-L-third coarse amino acid dissolves: get and accurately take N-FMOC-L-third coarse amino acid, and be placed in off-the-shelf ethanol/water system (ethanol/water=3: 2) solution are housed, be mixed with N-FMOC-L-third amino acid that concentration is 50.1 (g/l), and shake well, then, be placed in the water-bath reaching design temperature, until N-FMOC-L-third amino acid is completely in dissolved state.
(4) N-FMOC-L-third amino acid crystallizes: under N-FMOC-L-third amino acid fully in dissolved state is placed in room temperature, spends the night, make its crystallization.
(5) N-FMOC-L-third amino acid crystallizes process: filter N-FMOC-L-third amino acid crystallizes with suction filter, and with ethanol/water system (ethanol/water=3: 2) solution rinses more than 3 times repeatedly, take N-FMOC-L-third amino acid crystallizes, be placed on seasoning in moisture eliminator, weigh dry rear FMOC-L-third amino acid crystallizes (under high performance liquid phase 254nm purity >=99.67), calculated yield (90.3%).
(6) ethanol reclaims: by residual solvent after suction filtration N-FMOC-L-third amino acid crystallizes, be placed in water distilling apparatus, and setting distillation parameter, reclaims ethanol.
embodiment 2FMCO-L-leucine purification process
(1) ethanol/water system solution prepares: according to object N-FMOC-L-leucin crystallization requirement, preparation ethanol/water=2: 3 system solutions.
(2) attemperator prepares: in water bath, add appropriate water, after switching on power, and setting water bath temperature, and be heated to setting 80 DEG C.
(3) N-FMOC-L-leucin dissolving crude product: get and accurately take N-FMOC-L-leucin crude product, and be placed in off-the-shelf ethanol/water system (ethanol/water=2: 3) solution are housed, be mixed with the N-FMOC-L-leucin that concentration is 27.3 (g/l), and shake well, then, be placed in the water-bath reaching design temperature, until N-FMOC-L-leucin is completely in dissolved state.
(4) N-FMOC-L-leucin crystallization: under the N-FMOC-L-leucin fully in dissolved state is placed in room temperature, spends the night, make its crystallization.
(5) N-FMOC-L-leucin crystallization treatment: filter the crystallization of N-FMOC-L-leucin with suction filter, and with ethanol/water system (ethanol/water=2: 3) solution rinses more than 3 times repeatedly, take the crystallization of N-FMOC-L-leucin, be placed on seasoning in moisture eliminator, weigh dry rear FMOC-L-leucin crystallization (under high performance liquid phase 254nm purity >=99.73), calculated yield (93.9%).
(6) ethanol reclaims: by suction filtration N-FMOC-L-leucin remaining after crystallization solvent, be placed in water distilling apparatus, and setting distillation parameter, reclaims ethanol.
embodiment 3FMCO-L-Isoleucine purification process
(1) ethanol/water system solution prepares: according to object N-FMOC-L-different leucin crystallization requirement, preparation ethanol/water=1: 1 system solution.
(2) attemperator prepares: in water bath, add appropriate water, after switching on power, and setting water bath temperature, and be heated to setting 80 DEG C.
(3) N-FMOC-L-different leucin dissolving crude product: get and accurately take the different leucin crude product of N-FMOC-L-, and be placed in off-the-shelf ethanol/water system (ethanol/water=1: 1) solution is housed, be mixed with the different leucin of N-FMOC-L-that concentration is 53.8 (g/l), and shake well, then, be placed in the water-bath reaching design temperature, until the different leucin of N-FMOC-L-is completely in dissolved state.
(4) N-FMOC-L-different leucin crystallization: under the different leucin of N-FMOC-L-fully in dissolved state is placed in room temperature, spends the night, make its crystallization.
(5) N-FMOC-L-different leucin crystallization treatment: filter the different leucin crystallization of N-FMOC-L-with suction filter, and with ethanol/water system (ethanol/water=1: 1) solution rinses more than 3 times repeatedly, take the different leucin crystallization of N-FMOC-L-, be placed on seasoning in moisture eliminator, weigh the dry rear different leucin crystallization of FMOC-L-(under high performance liquid phase 254nm purity >=99.19), calculated yield (86.4%).
(6) ethanol reclaims: by different for suction filtration N-FMOC-L-leucin remaining after crystallization solvent, be placed in water distilling apparatus, and setting distillation parameter, reclaims ethanol.
embodiment 4FMCO-L-methionine(Met) purification process
(1) ethanol/water system solution prepares: according to object N-FMOC-L-egg amino acid crystallization requirement, preparation ethanol/water=2: 3 system solutions.
(2) attemperator prepares: in water bath, add appropriate water, after switching on power, and setting water bath temperature, and be heated to setting 80 DEG C.
(3) N-FMOC-L-egg amino acid dissolving crude product: get and accurately take N-FMOC-L-egg amino acid crude product, and be placed in off-the-shelf ethanol/water system (ethanol/water=2: 3) solution are housed, be mixed with the N-FMOC-L-egg amino acid that concentration is 25.0 (g/l), and shake well, then, be placed in the water-bath reaching design temperature, until N-FMOC-L-egg amino acid is completely in dissolved state.
(4) N-FMOC-L-egg amino acid crystallization: under the N-FMOC-L-egg amino acid fully in dissolved state is placed in room temperature, spends the night, make its crystallization.
(5) N-FMOC-L-egg amino acid crystallization treatment: filter the crystallization of N-FMOC-L-egg amino acid with suction filter, and with ethanol/water system (ethanol/water=2: 3) solution rinses more than 3 times repeatedly, take the crystallization of N-FMOC-L-egg amino acid, be placed on seasoning in moisture eliminator, weigh dry rear FMOC-L-egg amino acid crystallization (under high performance liquid phase 254nm purity >=99.67), calculated yield (86.8%).
(6) ethanol reclaims: by suction filtration N-FMOC-L-egg amino acid remaining after crystallization solvent, be placed in water distilling apparatus, and setting distillation parameter, reclaims ethanol.
embodiment 5FMCO-L-glycine purification process
(1) ethanol/water system solution prepares: according to the sweet amino acid crystallizes requirement of object N-FMOC-L-, preparation ethanol/water=4: 5 system solutions.
(2) attemperator prepares: in water bath, add appropriate water, after switching on power, and setting water bath temperature, and be heated to setting 80 DEG C.
(3) the sweet coarse amino acid of N-FMOC-dissolves: get and accurately take the sweet coarse amino acid of N-FMOC-, and be placed in off-the-shelf ethanol/water system (ethanol/water=4: 5) solution are housed, be mixed with the sweet amino acid of N-FMOC-that concentration is 22.2 (g/l), and shake well, then, be placed in the water-bath reaching design temperature, until the sweet amino acid of N-FMOC-is completely in dissolved state.
(4) the sweet amino acid crystallizes of N-FMOC-: under the sweet amino acid of N-FMOC-fully in dissolved state is placed in room temperature, spends the night, make its crystallization.
(5) N-FMOC-sweet amino acid crystallizes process: filter the sweet amino acid crystallizes of N-FMOC-with suction filter, and with ethanol/water system (ethanol/water=4: 5) solution rinses more than 3 times repeatedly, take the sweet amino acid crystallizes of N-FMOC-, be placed on seasoning in moisture eliminator, weigh the dry rear sweet egg amino acid crystallization of FMOC-L-(under high performance liquid phase 254nm purity >=99.59), calculated yield (90.7%).
(6) ethanol reclaims: by residual solvent after sweet for suction filtration N-FMOC-amino acid crystallizes, be placed in water distilling apparatus, and setting distillation parameter, reclaims ethanol.
embodiment 6FMCO-L-phenylalanine purification process
(1) ethanol/water system solution prepares: according to the requirement of object N-FMOC-L-phenylpropyl alcohol amino acid crystallizes, preparation ethanol/water=2: 1 system solution.
(2) attemperator prepares: in water bath, add appropriate water, after switching on power, and setting water bath temperature, and be heated to setting 80 DEG C.
(3) N-FMOC-phenylpropyl alcohol coarse amino acid dissolves: get and accurately take N-FMOC-L-phenylpropyl alcohol coarse amino acid, and be placed in off-the-shelf ethanol/water system (ethanol/water=2: 1) solution are housed, be mixed with the N-FMOC-L-phenylpropyl alcohol amino acid that concentration is 42.7 (g/l), and shake well, then, be placed in the water-bath reaching design temperature, until N-FMOC-L-phenylpropyl alcohol amino acid is completely in dissolved state.
(4) N-FMOC-L-phenylpropyl alcohol amino acid crystallizes: under the N-FMOC-L-phenylpropyl alcohol amino acid fully in dissolved state is placed in room temperature, spends the night, make its crystallization.
(5) N-FMOC-L-hydrocinnamyl acid crystal process: filter N-FMOC-L-phenylpropyl alcohol amino acid crystallizes with suction filter, and with ethanol/water system (ethanol/water=2: 1) solution rinses more than 3 times repeatedly, take N-FMOC-L-phenylpropyl alcohol amino acid crystallizes, be placed on seasoning in moisture eliminator, weigh dry rear FMOC-L-phenylpropyl alcohol amino acid crystallizes (under high performance liquid phase 254nm purity >=99.15), calculated yield (87.8%).
(6) ethanol reclaims: smooth out with the fingers residual solvent after suction filtration N-FMOC-L-phenylpropyl alcohol amino acid crystallizes, be placed in water distilling apparatus, and setting distillation parameter, reclaims ethanol.
embodiment 7FMCO-L-α-amino-isovaleric acid purification process
(1) ethanol/water system solution prepares: according to the requirement of object N-FMOC-L-figured silk fabrics amino acid crystallizes, preparation ethanol/water=2: 3 system solutions.
(2) attemperator prepares: in water bath, add appropriate water, after switching on power, and setting water bath temperature, and be heated to setting 80 DEG C.
(3) N-FMOC-L-figured silk fabrics coarse amino acid dissolves: get and accurately take N-FMOC-figured silk fabrics coarse amino acid, and be placed in off-the-shelf ethanol/water system (ethanol/water=2: 3) solution are housed, be mixed with the N-FMOC-L-figured silk fabrics amino acid that concentration is 26.4 (g/l), and shake well, then, be placed in the water-bath reaching design temperature, until N-FMOC-L-figured silk fabrics amino acid is completely in dissolved state.
(4) N-FMOC-figured silk fabrics amino acid crystallizes: under the N-FMOC-L-figured silk fabrics amino acid fully in dissolved state is placed in room temperature, spends the night, make its crystallization.
(5) N-FMOC-figured silk fabrics base acid crystal process: filter N-FMOC-L-figured silk fabrics amino acid crystallizes with suction filter, and with ethanol/water system (ethanol/water=2: 3) solution rinses more than 3 times repeatedly, take N-FMOC-L-figured silk fabrics amino acid crystallizes, be placed on seasoning in moisture eliminator, weigh dry rear FMOC-L-figured silk fabrics amino acid crystallizes (under high performance liquid phase 254nm purity >=99.97), calculated yield (89.9%).
(6) ethanol reclaims: by residual solvent after suction filtration N-FMOC-L-figured silk fabrics amino acid crystallizes, be placed in water distilling apparatus, and setting distillation parameter, reclaims ethanol.
embodiment 8FMCO-L-proline(Pro) purification process
(1) ethanol/water system solution prepares: according to the requirement of object N-FMOC-L-dried meat amino acid crystallizes, preparation ethanol/water=2: 3 system solutions.
(2) attemperator prepares: in water bath, add appropriate water, after switching on power, and setting water bath temperature, and be heated to setting 80 DEG C.
(3) N-FMOC-figured silk fabrics coarse amino acid dissolves: get and accurately take N-FMOC-L-dried meat coarse amino acid, and be placed in off-the-shelf ethanol/water system (ethanol/water=2: 3) solution are housed, be mixed with the N-FMOC-L-dried meat amino acid that concentration is 26.8 (g/l), and shake well, then, be placed in the water-bath reaching design temperature, until N-FMOC-L-dried meat amino acid is completely in dissolved state.
(4) N-FMOC-dried meat amino acid crystallizes: under the N-FMOC-L-dried meat amino acid fully in dissolved state is placed in room temperature, spends the night, make its crystallization.
(5) N-FMOC-L-figured silk fabrics base acid crystal process: filter N-FMOC-L-dried meat amino acid crystallizes with suction filter, and with ethanol/water system (ethanol/water=2: 3) solution rinses more than 3 times repeatedly, take N-FMOC-L-dried meat amino acid crystallizes, be placed on seasoning in moisture eliminator, weigh dry rear N-FMOC-L-dried meat amino acid crystallizes (under high performance liquid phase 254nm purity >=99.27), calculated yield (87.9%).
(6) ethanol reclaims: by residual solvent after suction filtration N-FMOC-L-dried meat amino acid crystallizes, be placed in water distilling apparatus, and setting distillation parameter, reclaims ethanol.
Above content is in conjunction with concrete preferred version mode detailed description made for the present invention, but can not assert that the present invention is confined to these.For those skilled in the art, without departing from the inventive concept of the premise, some simple deduction or replace can also be made, all should be considered as belonging to protection scope of the present invention.The ratio of ethanol/water system as described in claim 4 is ethanol: water=1 ~ 5: 1 ~ 7; The N-FMOC-amino acid solution concentration be mixed with described in claim 5 is 10 ~ 70 (g/l); The temperature of heating in water bath according to claim 6 is 50 ~ 90 DEG C.
Claims (5)
1.
for a method for the N-FMOC-coarse amino acid crystallization of non-active side chain, comprise the following steps:
1) be dissolved in ethanol-water system by N-FMOC-coarse amino acid, be mixed with N-FMOC-amino acid solution, under condition of water bath heating, vibration makes it dissolve completely;
2) N-FMOC-amino acid crystallizes is made, suction filtration crystalline mother solution at step 1) gained solution being placed in 12 DEG C-16 DEG C, with the abundant wash crystallization of ethanol-water system of preparation, and dry N-FMOC-amino acid crystallizes sterling;
3) by step 2) in residual solvent after suction filtration N-FMOC-amino acid crystallizes, be placed in water distilling apparatus, Distillation recovery ethanol;
the N-FMOC-amino acid of described non-active side chain comprises: N-FMCO-L-L-Ala, N-FMCO-L-phenylalanine, N-FMCO-L-leucine, N-FMCO-L-Isoleucine, N-FMCO-glycine, N-FMCO-L-methionine(Met), N-FMCO-L-α-amino-isovaleric acid, N-FMCO-L-proline(Pro).
2.
method described in claim 1, is characterized in that: adopt ethanol-water system as washings, wherein not containing sherwood oil toxic organic solvents.
3.
method described in claim 1, is characterized in that: the ratio of ethanol-water system described in step 1) is ethanol: water=1 ~ 4:1 ~ 5.
4.
method according to claim 1, the N-FMOC-amino acid solution concentration be wherein mixed with described in step 1) is 22 ~ 55g/l.
5.
method according to claim 1, wherein the temperature of heating in water bath described in step 1) is 60 ~ 80 DEG C.
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| CN113880731A (en) * | 2021-10-28 | 2022-01-04 | 成都市科隆化学品有限公司 | Fmoc-D-Cit optical purity purification method and obtained product |
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| JPH05112576A (en) * | 1991-10-21 | 1993-05-07 | Hitachi Chem Co Ltd | New dopa derivative and its production |
| CN1589257A (en) * | 2001-11-15 | 2005-03-02 | 舍林股份公司 | N-methyl-homocysteines and their use as well as process for their production |
| CN101962351A (en) * | 2010-09-27 | 2011-02-02 | 华东理工大学 | Alpha-amino acid derivatives and preparation method, intermediate and application thereof |
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| JPH05112576A (en) * | 1991-10-21 | 1993-05-07 | Hitachi Chem Co Ltd | New dopa derivative and its production |
| CN1589257A (en) * | 2001-11-15 | 2005-03-02 | 舍林股份公司 | N-methyl-homocysteines and their use as well as process for their production |
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